Cedazuridine

Cedazuridine Uses, Dosage, Side Effects, Food Interaction and all others data.

Myelodysplastic syndromes (MDS) are a group of hematopoietic neoplasms that give rise to variable cytopenias progressing to secondary acute myeloid leukemia (sAML), which is invariably fatal if untreated. Hypomethylating agents such as decitabine and azacitidine are used to treat MDS through inducing DNA hypomethylation and apoptosis of cancerous cells. Although effective, these compounds are rapidly metabolized by cytidine deaminase (CDA) prior to reaching systemic circulation when administered orally, necessitating intramuscular or intravenous administration routes. Cedazuridine is a fluorinated tetrahydrouridine derivative specifically designed to inhibit CDA and facilitate oral administration of hypomethylating agents.

Cedazuridine was first reported in 2014, and was subsequently approved by the FDA on July 7, 2020, in combination with decitabine for sale by Astex Pharmaceuticals Inc under the name INQOVI®.

Cedazuridine is a cytidine deaminase inhibitor that is co-administered with hypomethylating agents such as decitabine in order to increase their oral bioavailability. In combination with hypomethylating agents, cedazuridine may cause myelosuppression and embryo-fetal toxicity and should be administered with appropriate monitoring.

Cedazuridine
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Cedazuridine
Generic	Cedazuridine
Cedazuridine Other Names	Cedazuridine
Type
Formula	C₉H₁₄F₂N₂O₅
Weight	Average: 268.217 Monoisotopic: 268.087077885
Protein binding	Neither decitabine nor cedazuridine display appreciable plasma protein binding. The bound fraction of decitabine between doses of 17 and 342 ng/mL was between 2 and 4%, while that of cedazuridine for doses between 1000 ng/mL and 50000 ng/mL was between 2 and 6%.
Groups	Approved, Investigational
Therapeutic Class
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

Uses

Cedazuridine is a cytidine deaminase inhibitor coadministered with the hypomethylating agent decitabine for the treatment of variable forms of myelodysplastic syndrome (MDS).

Cedazuridine, in combination with decitabine, is indicated for the treatment of myelodysplastic syndromes (MDS), including MDS with refractory anemia, MDS with refractory anemia and ringed sideroblasts, MDS with refractory anemia and excess blasts, MDS scoring intermediate-1, intermediate-2, or high-risk on the International Prognostic Scoring System (IPSS), and chronic myelomonocytic leukemia (CMML).

Cedazuridine is also used to associated treatment for these conditions: Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes (MDS)

How Cedazuridine works

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematopoietic neoplasms arising from a variety of underlying mutations that manifest in peripheral cytopenias and may eventually progress to secondary acute myeloid leukemia (sAML). There are over 45 genes commonly mutated in MDS patients, including those involved in DNA methylation and repair, histone modification, RNA splicing, transcription, signal transduction, and cellular adhesion. It is hypothesized that initial clonal founder mutations give rise to progressive acquisition of secondary mutations and facilitate disease progression to sAML.

Hypomethylating agents such as decitabine are metabolized into triphosphate derivatives that are subsequently incorporated into DNA. Once incorporated, these agents inhibit the activity of DNA methylases such as DNMT1, leading to progressive DNA hypomethylation and eventual activation of tumour suppression genes and apoptotic pathways. However, hypomethylating agents given orally are vulnerable to first-pass metabolism by cytidine deaminase, and hence typically have to be administered through intramuscular or intravenous routes. Co-administration with cedazuridine, which is an efficient inhibitor of cytidine deaminase, drastically increases the oral bioavailability of decitabine, allowing for combination oral therapy.

Toxicity

Cedazuridine administered orally to mice in 7 days on/21 days off cycles for a total of 91 days in doses of 100, 300, or 1000 mg/kg produced abnormal effects only at the 1000 mg/kg dose, which is roughly 108 times the recommended dose in humans. These effects included abnormal histology of the testes, epididymis, and ovaries, as well as decreased sperm count; these effects were reversible following cedazuridine removal.

Food Interaction

Take on an empty stomach. Avoid consuming food for both two hours before and after each dose.

Volume of Distribution

The apparent volume of distribution (and coefficient of variation) of decitabine and cedazuridine at steady state was 417 (54%) and 296 (51%), respectively.

Elimination Route

Cedazuridine (100 mg) taken orally with decitabine (35 mg) once daily for five days resulted in a day 1 AUC and steady-state AUC (coefficient of variation) of 103 (55%) and 178 (53%) ng*hr/mL for decitabine and 2950 (49%) and 3291 (45%) ng*hr/mL for cedazuridine, respectively. Overall, the 5-day cumulative AUC for decitabine was 851 (50%). Similarly, the C_max for decitabine and cedazuridine was 145 (55%) and 371 (52%) ng/mL, respectively. The median T_max for decitabine was 1 hr (range 0.3 to 3.0 hrs) and for cedazuridine was 3 hrs (range 1.5 to 6.1 hrs).

The bioavailability of decitabine, as assessed by comparing the AUC of oral decitabine co-administered with cedazuridine to intravenous decitabine alone, was 60% on day 1 (90% CI of 55-65%). The corresponding values on day 5 and considering the cumulative day 5 dose were 106% (90% CI: 98, 114) and 99% (90% CI: 93, 106). Hence, the oral bioavailability of decitabine approaches 100% over the 5-day treatment cycle.